del(8p) and TNFRSF10B loss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia

  • Leukemia. 2023 Sep 26. doi: 10.1038/s41375-023-02035-3.
Ludovic Jondreville  1 ,  Lea Dehgane  1 ,  Cecile Doualle  1 ,  Luce Smagghe  1 ,  Beatrice Grange  2 ,  Frederic Davi  1  2 ,  Leticia K Lerner  1 ,  Delphine Garnier  1 ,  Clotilde Bravetti  1  2 ,  Olivier Tournilhac  3 ,  Damien Roos-Weil  1  4 ,  Marouane Boubaya  5 ,  Elise Chapiro  6  7 ,  Santos A Susin  8 ,  Florence Nguyen-Khac  9  10
Affiliations
  • 1. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France.
  • 2. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Sorbonne Université, AP-HP, Paris, France.
  • 3. Service d'Hématologie Clinique, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand, France.
  • 4. Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
  • 5. Unité de Recherche Clinique, Hôpitaux Universitaires Paris Seine-Saint-Denis, AP-HP, Bobigny, France.
  • 6. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France. [email protected].
  • 7. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Sorbonne Université, AP-HP, Paris, France. [email protected].
  • 8. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France. [email protected].
  • 9. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France. [email protected].
  • 10. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Sorbonne Université, AP-HP, Paris, France. [email protected].
PMID: 37752286 DOI: 10.1038/s41375-023-02035-3
Abstract

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal abnormality (del(8p), deletion of the short arm of chromosome 8) in the context of CLL. By comparing the largest cohort of del(8p) CLL to date (n = 57) with a non-del(8p) cohort (n = 155), del(8p) was significantly associated with a poor prognosis, a shorter time to first treatment, worse overall survival (OS), and a higher risk of Richter transformation. For patients treated with fludarabine-based regimens, the next-treatment-free survival and the OS were shorter in del(8p) cases (including those with mutated IGHV). One copy of the TNFRSF10B gene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10B was haploinsufficient in del(8p) CLL, and was involved in the modulation of fludarabine-induced cell death - as confirmed by our experiments in primary cells and in CRISPR-edited TNFRSF10B knock-out CLL cell lines. Lastly, del(8p) abrogated the synergy between fludarabine and TRAIL-induced Apoptosis. Our results highlight del(8p)'s value as a prognostic marker and suggest that fit CLL patients (i.e. with mutated IGHV and no TP53 disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.

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